The overall objective of this grant is to develop a non-invasive method for assessment of insulin resistance and impaired glucose tolerance (IGT) as a measure of pre-diabetes suitable for application to large-scale screening studies and to individualized preventive strategies in patients at risk for development of diabetes. This new approach is based on the known alterations in the mix of whole-body fuel utilization that occurs during progression from normal glucose tolerance to impaired glucose tolerance to diabetes. It involves administration of a standard oral glucose tolerance test solution that contains, in addition, a small quantity of the non-radioactive (stable isotope) 13C6-glucose, followed by measurement of breath 13CO2 isotope enrichment. During Phase-I of this project, we have established the proof-of-concept and feasibility of this approach. We have demonstrated that the correlation of the said method with the common indices of insulin resistance possesses similar statistical strength compared with those published for these indices and the currently accepted gold standard, i.e. the glucose-clamp. We have also demonstrated that inter-individual reproducibility of the breath test as a measure of IGT is acceptably low and its correlation with OGTT sufficiently high to permit its development as a non-invasive test of IGT. During Phase-II, we will conduct a number of clinical investigations to: 1) evaluate the intra- and inter-individual variability of our method compared to the glucose-clamp, the three common indices (HOMA-IR, QUICKI, and WBISI), and the standard OGTT;and 2) to evaluate the correlation between our proposed breath test, the glucose-clamp, common indices, and OGTT in individuals whose glycemia ranges from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to diabetes and whose body mass index (BMI) covers the range from lean to obese. We anticipate that successful completion of the Phase-II research will lead to the development of a routine method for assessment of insulin resistance and a non-invasive test of IGT for application to screening and individualized preventive studies. After successful completion of Phase-II research and with non-SBIR funding, we will establish a central facility to produce and market appropriate "test kit(s)" along with the necessary analytical expertise - making the method available to all interested parties for clinical or research purposes. PUBLIC HEALTH RELEVANCE: Insulin resistance and impaired glucose tolerance are early manifestations of serious chronic disorders of major concern to public health: diabetes, chronic heart disease, obesity, hypertension, etc. Their early recognition is important for preventive purposes. Currently, the "Gold Standard" for assessing insulin resistance is the so-called glucose-clamp, which is not suitable for general-purpose clinical management of patients. The surrogate methods available currently, the so-called Common indices show large inter- individual variability's for any given value of their corresponding glucose-clamp and, thus, are not suitable for individualized preventive purposes. During Phase-I of this SBIR program, we have demonstrated that a non- invasive Breath Test has the potential to be a suitable surrogate test for the glucose-clamp and as a non- invasive measure of impaired glucose tolerance (pre-diabetes). During Phase-II, we propose to develop this test and to demonstrate its high linear correlation with both the glucose-clamp and oral glucose tolerance test.